Examination of the in vivo cardiac electrophysiological effects of nesiritide (human brain natriuretic peptide) in conscious dogs.

BACKGROUND: Human brain natriuretic peptide (hBNP) is a new therapeutic agent, nesiritide, indicated in patients with decompensated congestive heart failure, a group at significant risk of developing cardiac arrhythmias. Whether hBNP has cardiac electrophysiologic effects has not been reported. METHODS AND RESULTS: In 9 healthy, chronically instrumented, conscious dogs, hemodynamic and electrophysiologic parameters were assessed at baseline and during recombinant hBNP (nesiritide) infusion at 0.03 and 0.09 microg/kg/min after 1 hour at each dose. Infusion of hBNP produced dose-related increases (P <.001) in hBNP and cyclic GMP plasma levels and reductions (P <.05) in mean arterial pressure. Mean central venous pressure and sinus cycle length did not change significantly. Infusion of hBNP produced no significant changes in any of the electrophysiologic parameters including no change in surface ECG variables (P wave duration, PR interval, QRS duration, and QTc interval), corrected sinus node recovery time, atrioventricular nodal Wenckebach cycle length, and atrial and ventricular effective refractory periods measured at a 400 ms cycle length. Spontaneous or induced arrhythmias were not observed during hBNP infusion. CONCLUSIONS: In conscious, healthy dogs, short-term infusion of recombinant hBNP has no significant effects on atrial or ventricular electrophysiologic parameters.

Summary of a symposium on natriuretic and digitalis-like factors.

An international symposium on natriuretic and digitalis-like factors was convened for the first time since 1992. Topics discussed included structures and biosynthesis of endogenous digitalis-like factors (EDLF), biologic activities, physiology function and role of EDLF in hypertension, and novel natriuretic factors. Progress was reported in determining the exact structure of an isomer of ouabain isolated from bovine hypothalamus. Evidence was presented supporting the existence of a second mammalian EDLF that resembles steroids found in toads (bufodienolides). Support for endogenous synthesis of mammalian EDLF was also presented. Mammalian EDLF were reported to have effects which are different from those possessed by digitalis like steroids derived from plants. New evidence was presented implicating EDLF in various forms of hypertension in humans and animal models. Finally, several unique natriuretic factors that do not inhibit Na, K ATPase and that appear to play a role in mammalian volume regulation were discussed.

Partial purification of a sodium pump inhibitor from bovine adenohypophysis. Its comparison with the natriuretic factor isolated from hypothalamus.

Adenohypophysis and hypothalamic bovine tissues were homogenized, lipid extracted, salt removed and loaded onto 2 successive mu Bondapak HPLC columns, semipreparative and analytic, respectively. In vitro sodium-pump inhibitory activity, recovered from each tissue, showed similar chromatographic patterns, but hypothalamus seems to contain a major hydrophobic material which appears at the end of the run, when acetonitrile gradient raised 40% approximately. Digitalis-like activity disappears along the purification procedure, and this fact suggests a clear dissociation between (Na/K)ATPase inhibition and digoxin-like activity, measured as crossing with digoxin antibodies.

The search for a hypothalamic Na+,K+-ATPase inhibitor.

Accumulating experimental evidence suggests that natriuresis in response to intravascular volume expansion is promoted by an endogenous regulator of Na+,K+-adenosine triphosphatase (ATPase). Efforts to purify this substance by a number of laboratories have as yet been unsuccessful. The properties of partially purified inhibitors from plasma, urine, and tissue often fail to possess the characteristics thought to be consistent with those of a physiological regulator. These include potency (Ki of approximately 1 nM), reversibility of inhibition, specificity for Na+,K+-ATPase, and responsiveness to relevant physiological stimuli. Two rather different candidate substances, extracted from urine and hypothalamus, have been purified to a high degree. Neither is a peptide, and both are of low molecular weight and resistant to acid hydrolysis. The substance from urine is rather nonpolar and interacts with digoxin-specific antibodies, while that from hypothalamus is polar and does not appear to share epitopes with the cardiac glycosides. On the serosal surface of the toad urinary bladder, the hypothalamic substance causes a reversible inhibition of Na+ transport, inhibits rubidium uptake in red blood cells by acting on the membrane's exterior surface, inhibits binding of ouabain to purified Na+,K+-ATPase, and reversibly inhibits hydrolysis of adenosine 5'-triphosphate by the enzyme with a Ki of 1.4 nM. The hypothalamic inhibitor may be differentiated from ouabain by their respective ionic requirements for optimal inhibition of enzymatic activity, and although both ouabain and the hypothalamic inhibitor fix Na+,K+-ATPase in its E2 conformation, the hypothalamic inhibitor does not promote phosphorylation of the enzyme by inorganic phosphate in the presence of Mg2+. Ionic requirements for inhibition also differentiate the hypothalamic inhibitor from vanadate ion, as does the inhibitor's activity in the presence of norepinephrine. Further enzymological and physiological studies will be facilitated by structural characterizations of the inhibitory substances and by the availability of a method to measure their concentrations in physiological fluids.